Injectable tetramisole compositions

ABSTRACT

Aqueous injectable solutions of tetramisole which comprise tetramisole citrate, tartrate, or phosphate equivalent to at least 6 percent w/v of L-tetramisole base, the pH of the solution being adjusted to the range of from 2 to 4 by addition of tartaric, citric or phosphoric acid.

United States Patent Pryor et a]. 1 June 13, 1972 [54] INJECTABLETETRAMISOLE [58] Field of Search ..424/270 COMPOSITIONS [72] Inventors:David Ernest Pryor, Balwyn, Victoria; [56] References Cmd Bruce AdamForsyth, Croydon, Victoria, OTHER PUBLICATIONS both of Australia MerckIndex- Eighth edit. 1968) page 1,029 [73] Asslgnee: Imperial ChenucalIndustries of Australia i q N P Lmmed Melbourne Primary Examiner-SamRosen 1c r Attorney-Cushman, Darby & Cushman [22] Filed: July 13, 1970[2]] Appl. No.: 54,642 ABSTRACT Aqueous injectable solutions oftetramisole which comprise 30 A u a D8 tetramisole citrate, taxtrate, orphosphate equivalent to at Forelgn pp ca T Pnomy least 6 percent w/v ofL-tetramisole base, the pH of the solu- Jllly 21, 1969 Australia [ionadjuged to the range of from 2 to 4 by addition of tartaric, citric orphosphoric acid. [52] U.S. CI ..424/270 [51] Int. Cl. ..A6lk 27/00 8Claims, No Drawings INJECTABLE TETRAMISOLE COMPOSITIONS This inventionrelates to new formulations of tetrarnisole; in particular it relates toformulations which are suitable for administration by injection intowarm-blooded animals, e.g. cattle, pigs, sheep or fowl. it is known fromBritish Pat. No. 1,043,489 Janssen Pharmaceutica N.V. that D,L-2,3,5,6-tetrahydro-6-phenylimidazo-(2,l-b)-thiazole (for convenience hereinafterreferred to as D,L-tetramisole) and its therapeutically acceptable acidaddition salts are potent anthelmintic agents. The said specificationBrit. Pat. No. 1,043,489 enumerates many acid addition salts of D,L-tetrarnisole derived from common organic and inorganic acids. It is alsoknown that laevorotatory tetrarnisole, hereinafter referred to asL-tetramisole, is approximately twice as active as D,L-tetramisole as ananthelmintic agent, i.e. that L-tetramisole is responsible for all ormost of the anthelmintic activity, at least in ruminants such as sheepor cattle. in our Australian Pat. application No. 32285/68 we havedisclosed and claimed a process for preparing L- tetramisole in highlypure form. Since the mammalian tolerance to dextrorotatory tetrarnisole(hereinafter referred to as D-tetramisole) is approximately equal to thetolerance of L-tetramisole, the manufacture of pure L-tetramisole madeit possible to substantially reduce the risk of toxic reaction in thehost animal. Although the D,L-tetramisole racemate itself has a widesafety margin for most species, the practically doubled safety margin ofthe L-isomer has great value when it is administered under varyingcontrol in the field, particularly under the extremes of conditions ofsheepand cattle-farming in the Australian outback or in the open rangesin the U.S.A., where prolonged drought may unpredictably reduce theresistance of individual animals. Furthermore, preparation of pureL-tetramisole facilitated administration by subcutaneous injection sincelower dosages are required.

In spite of the fact that tetrarnisole can be administered per os,administration by injection is a desirable objective. Cattle,particularly wild range cattle, resist the administration of drugs perand complex harnessing equipment is required for satisfactory handling.The administration of the drug to cattle by injection is far simpler,permits the dosing of many more animals per unit of time and involvesfar less risk to man and animal; even with sheep, pigs or poultry,injection is at times preferable. However, the administration oftetrarnisole solutions by injection has not proved entirelysatisfactory. With cattle the therapeutic dose injected is proportionalto body weight and therefore relatively large. A very small proportionof the animals exhibits sensitivity and even undesirable pathologicalreactions at the site of injection varying from mild irritation to theformation of lumps, which may range in diameter from several millimetersup to several centimeters.

Although the statistical incidence of this phenomenon is extremely lowit has up to date prevented the adoption of administration by injectionin many areas and the elimination of this phenomenon remains thereforehighly desirable. In the widespread application of tetrarnisole in manycountries, almost universally, its halide, particularly its chloridesalts have been used for aqueous formulations, mostly with smalladditions of phosphate or citrate buffer, usually less than 0.03mol/liter, to control the pH to somewhat less than the normal pH of thehydrochloride, which is at about 4. This pH adjustment has been madesolely for the purpose of improving the storage stability of thesolutions, since tetrarnisole undergoes base-catalysed hydrolysis to aninactive derivative.

The pathological sensitivity observed with certain animals afterinjection of the hydrochloride has hitherto been ascribed toidiosyncratic reactions to the organic tetrarnisole molecule, e.g.irritancy or histaminic releases.

For this reason considerations of biological acceptability, particularlyacceptability for injections, hitherto have concentrated on the effectof the tetrarnisole molecule or analogues thereof.

We have now found that the requirements for therapeutic acceptability oftetrarnisole salts for injection differs from those for administrationper os." In particular we have discovered that the anion of thetetrarnisole salt in the solution affects the living tissue to varyingdegrees. While we do not wish to be limited by theory we consider thatosmotic and/or electro-osmotic effects in certain sensitive animals canprovide the driving force to damage in the cell walls and that this canbe remedied by the selection of a suitable anion for the tetrarnisolesalt.

We have found furthennore that a measure of the therapeuticacceptability for injections of aqueous tetrarnisole addition saltsolutions can be obtained by a simple haemolysis test. When one of thetetrarnisole salts which is less acceptable for subcutaneous injectionis mixed with bovine blood under standard conditions, a proportion ofthe red blood cells undergoes haemolysis, and blood serum becomescolored to a degree, varying with the degree of haemolysis. No or verylittle such.

haemolysis is observed with salts acceptable for injection. If the redblood cells are then removed by centrifugation of the solution, theresidual color of the blood serum is a quantitative measure of thehaemolysis. While we do not know whether some haemolysis may occur invivo in the tissue of the animal or whether haemolysis in bloodexhibited in the in vitro test is merely a phenomenon correlated to thedamage of tissue in vivo, we have found that the degree of haemolysis iscorrelated significantly with the occurrence of sensitivity toinjections in those live animals which exhibit sensitivity totetramisole hydrochloride injections.

Accordingly we provide an aqueous solution of an amount of atetrarnisole salt equivalent to at least 6 percent w/v of L- tetramisolebase, which solution when mixed with bovine blood and subjected to thehaemolysis test hereinafter defined, does not produce haemolysis to anextent exceeding the rating S of said haemolysis test.

HAEMOLYSIS TEST The test is carried out on heparinised venous blooddrawn either from individual animals or, preferably, on a bulkedrepresentative sample from a number of the animals to be subsequentlyinjected.

Procedure Into a series of centrifuge tubes of at least 10 cc capacity,pipette 2 ml of the aqueous solution of the tetrarnisole salt to betested, add quickly with agitation 4 ml of whole heparinised venousblood and place the centrifuge tube in a water-bath at 38 C for 20minutes. Immediately centrifuge at a force at least 1,500 G s to throwdown the red cells and compare the color of the supernatant plasma witha series of standards prepared as follows:

Solution 1 Prepare a batch of bovine serum preferably from the sameblood by centrifuging unhaemolysed blood as described above.

Solution 2 Prepare haemolysed blood by diluting 4 vols of blood with 2vols of 15 percent w/v tetrarnisole hydrochloride. Hold at 38 C for 20minutes.

Prepare standards by mixing solutions 1 and 2 in the ratios shown below.

A rating of zero corresponds to no haemolysis, and S to negligibleeffect; these ratings characterize the salts of the present invention.Ratings from 1 to express varying degrees of definite haemolysis up tofully haemolysed and are associated with the prior art salts which areless acceptable for injection.

Hitherto, the irritant properties of tetramisole salts, e.g. of thewidely used tetramisole hydrochloride, have imposed limitations on theconcentration of the drug which could be injected with the desired highdegree of safety, and have necessitated compromises between the volumeinjected and the therapeutic dose administered. Thus for some species ofworms, especially in the immature form, a higher dose rate is requiredfor complete control. A higher does can, of course, be provided by alarger injection volume or by a higher concentration, but with the saltsused hitherto in practice either of these alternatives exposes thetissues at the site of injection to higher risks of damage.

It is remarkable that the tetramisole salts used hitherto almostexclusively both for oral administration and injection,

namely the hydrochloride and, to a much lesser extent, the

acetate, are so much less acceptable for injection than the preferredsalts according to this invention.

We have found that the tetramisole salts satisfying the haemolysis test,e.g. citric acid, tartaric acid and, particularly, phosphoric acid aretherapeutically acceptable for injections; particularly acceptable andsuperior to all salts tested by us is the phosphoric acid salt and thisis therefore most preferred. Accordingly we provide an aqueous solutionof a tetramisole citrate, tartrate or phosphate equivalent to at least 6percent w/v of tetramisole base. With polyprotic acids of suitabledissociation constants, monoand di-tetramisole salts are acceptable butsome of the di-tetramisole salts, e.g. di-tetramisole phosphate arefairly alkaline and would lead to aqueous formulations having a pH inexcess of 5, e.g. in excess of the optimum desirable for storage in viewof the hydrolytic instability of tetramisole at pl-ls in excess of 5;consequently the addition of excess therapeutically acceptable anion,e.g. tartaric or phosphoric acid, is advisable, unless prolonged storageis not required. Accordingly out most preferred aqueous compositionscomprise tetramisole dihydrogen phosphate.

We have found furthermore that the solubility of L- tetramisoledihydrogen citrate, hydrogen tartrate and, particularly, L-tetramisoledihydrogen phosphate in water is. extremely high and that our biologicalfindings allow us to exploit this phenomenon in a new manner. Inparticular we have found that L-tetramisole dihydrogen phosphate issoluble at surprisingly high concentrations (in excess of 60 percent w/vat 0 C). Any reduction in the amount of injected fluid reducessensitivity marginally; however, with the tetramisole salt formulationsof the prior art a distinct increase in the incidence of irritation hasbeen associated with an increase in the concentration of the salt in theinjectable solutions. The tetramisole dihydrogen phosphate solutions, bycontrast, have been shown by us to be particularly acceptable at higherconcentrations. in addition there is some indication that the moreconcentrated phosphate salts exhibit improved therapeutic acceptabilityfrom the point of view of hyperaesthesia.

Accordingly we provide therapeutically acceptable injectable aqueoussolutions comprising L-tetramisole dihydrogen phosphate atconcentrations from 12.5 percent w/v up to the limit of its solubilityat the desired storage temperature. We have prepared and successfullyadministered solutions comprising up to and in excess of 50 percent w/vof tetramisole dihydrogen phosphate.

Because L-tetramisole is therapeutically more acceptable than theracemate and is a more concentrated form of the active ingredient it canbe administered in smaller amounts of injected fluid; our preferredsalts are therefore based on L- tetramisole, but salts of the racemateare included.

We have found furthermore that any residual undesirable side effects oftetramisole addition salts can be further reduced by the addition ofwater soluble and therapeutically acceptable salts, particularly sodiumsalts and we have confirmed that the solutions so prepared aretherapeutically more acceptable when injected into animals. The additionof these salts, especially of sodium salts, which is subject of ourcopending application of even date, may therefore be used as describedin said application to render the less preferred prior art tetramisolesolutions, e.g. tetramisole hydrochloride or tetramisole acetatesolutions, more acceptable; they may also be used to provide yet afurther, marginal but valuable improvement in the formulations of thepreferred tetramisole salts of this invention such as tetramisolecitrate, tartrate and, particularly the tetramisole phosphates. Suitablesodium salts are the salts of the anions which have been proved to betherapeutically more acceptable in the tetramisole salts themselvesnamely sodium citrate, sodium tartrate or sodium phosphate; again thesodium phosphates are more preferred and sodium dihydrogen phosphate ismost preferred. Other, less practical salts are the magnesium and, inthe low regions which are biologically permissible, potassium salts.Mixtures of suitable salts as defined may also be used. The monosodiumsalt is usually used although from the point of view of therapeutic andbiological acceptability the more alkaline salts are not excluded;however, they are not practical because of storage requirements in viewof the hydrolytic instability of tetramisole discussed above.

Accordingly we provide an aqueous injectable solution comprising atetramisole salt as hereinbefore defined in a concentration equivalentto at least 6 percent w/v of free tetramisole base and, in addition,from 0.1 to 0.5 inclusive moles, preferably from 0.15 to 0.5 inclusivemoles, of a water soluble sodium or potassium salt per liter ofsolution.

Whenever, as the result of the choice of a particular tetramisole saltor a particular sodium salt, the pH exceeds the optimum 4, the pH may beadjusted by the addition of an acid having a therapeutically acceptableanion, e.g. tartaric, citric or preferably phosphoric acid.

Accordingly we provide formulations as defined above wherein the pH isadjusted to the range from 2 to 4 by the addition of citric, tartaric orphosphoric acid.

We also provide a method of combatting helminthiasis in a warm-bloodedanimal which comprises injecting said animal with a tetramisole solutionas hereinbefore defined.

Our invention is now exemplified by but not limited to the followingexamples, in which all proportions are given as the weight/volumeequivalent to free tetramisole base, unless it is otherwise stated.

Examples 1 to 7 inclusive Sterile aqueous solutions, suitable forinjection were prepared from L-tetramisole dihydrogen phosphate, L-tetramisole hydrogen tartrate, L-tetramisole dihydrogen citrate,L-tetramisole acetate and L-tetramisole hydrochloride at theconcentrations stated in Tables 1 and 2. In addition to these salts thefollowing compounds which have been conventionally used in theprior-art-tetramisole formulations were added: 2 g sodium metabisulphite0.5 g methyl para-oxybenzoate, 0.05 g propyl para-oxybenzoate per 1,000mls of water.

From several large herds, cattle were selected which, during earliertrials, had shown sensitivity to tetramisole hydrochloride injections.This selection was necessary because the vast majority of animals showsno unfavorable reaction whatever to the injection of tetramisole and theincidence of sensitivity among normal cattle is so extremely low thatvery large numbers of cattle would need to be treated before anysignificant trends in irritation can be detected. It is known that quitegenerally the sensitivity to injections of any drug varies betweenanimals and, even for a given animal, varies from site to site ofinjection; to eliminate or minimize these side effects differenttreatments were randomised over sites as well as animals, using pairingof identical left and right side sites as much as possible forrandomisation. The sterile formulations were injected subcutaneously andthe hair was shaved off the injection sites to facilitate observation.

Assessments of the tissue reaction, if any, at the site of injectionwere made regularly for a period of up to 14 days. The type of reactionat each site was rated as follows:

0 No reaction Mild skin thickening and slight swelling of thesubcutaneous tissues, lower limit of detectability by palpation only.

2 Similar to rate 1 but slightly more extensive.

4 Swelling up to about 2" diameter visible,

slightly raised above the body surface.

8 Large swelling up to 4 in diameter and raised about to 1" above bodylevel.

16 Larger swelling than 8.

The exponential increase in the rating values takes into account theincreasing extent of the irritation. Ratings 0 to 4 inclusive, withoutshaving off the hair, would pass unnoticed in practice but ratings 8 andabove are noticeable and are undesirable; rating 16 is unacceptable.

Because a large number of treatments at one time cannot besatisfactorily paired and randomised with a manageable number ofanimals, and also to obtain an indication of random variation due toclimatic, biological (age, physical conditions, sex) and other chancefactors, several blocks of experiments were carried out and are reportedhere in separate tables. The sum of the ratings of the animals in eachgroup (total rating) divided by the number of animals gave the parameterrate/beast, which is an inverse expression of the acceptability of theinjectable formulation. Rates below 4.0 are satisfactory, below 2.0good, and below 1.5 excellent. All figures given in the tables werestatistically significant at the l in 100 level or better.

At the same time haemolysis tests were carried out as above described todetermine the correlation between the haemolysis and the acceptability,the rate/beast figure.

Results of experiments 1 to 7 inclusive are given in Tables 1 and 2;each table resulted from a separate block of experiments. Experiments 1to 4 are according to this invention, experiments S to 7 are accordingto the prior art.

Since, at conventional concentrations of L-tetramisole hydrochloride(6.38 percent w/v expressed as free base) even with selected sensitivetest animals, the incidence of irritation is too rare to be demonstratedin anything but very large-scale trials, the concentration ofL-tetrarnisole hydrochloride and acetate was increased (to 12.75 percentw/v expressed as free base) to increase sensitivity.

Examples 8 to 15 With prior art formulations it has been found thatsensitivity increases with increasing concentration of the tetramisolesalt, yet higher concentrations are desirable for greater ease ofadministration and efficacy against certain resistant strains ofinfestations.

To compare the increase in incidence of irritation with prior artformulations and with the formulations of the present invention, twoseries of experiments using progressively higher concentrations ofL-tetramisole were carried out in the manner described in Examples 1 to7 inclusive. Results, given in Tables 3 and 4, show that, with the priorart formulations of Table 3, using again selected animals of a known,relatively high sensitivity, the upper concentration limits at whichacceptability was excellent were exceeded rapidly; under identicalconditions the formulations according to the present invention of Table4, by contrast, established no upper limit of acceptability, even atmore than 5 times the concentration of the prior art formulationshitherto employed in practice. Thus, Table 4 demonstrates the excellentacceptability of the dihydrogen phosphate salt at very highconcentrations.

TABLE 3 Concentration (expressed as Exp. percent w./v. No. of Rate] No.L-tetramisole salt free base) beasts beast 8. Hydrochloride (prior art).15 36 5. 3 9 do 10 31 4. 1 10 .do 7. 5 14 2. 0

TABLE 4 Concentration (expressed as Exp. percent w./v. No. of Ratc/ No.L-tetramisole salt free base) beasts beast 11. Dihydrogen phosphate 42.3 2 1. 5 12- .....do 28.2 2 1.5 13. 21. 15 2 1. 5 14. 14. 1 2 1. 5 15-10. 5 2 0. 5

Examples 16 to 18 inclusive A further series of injections was carriedout as described in Examples 1 to 7, but in addition to theL-tetramisole dihydrogenphosphate a sodium salt was incorporated in theinjected solution (Exp. 17 and 18). Exp. 16 is a control according tothis invention, but without the sodium salt.

Results given in Table 5 show that a further highly desirable repressionof the irritation rate/beast was attained.

TABLE 5 Concentration (ex- Experiment pressed as percent Additive andconcentration, percent No. 01 Rate/ N 0. L-tetramisolc salt w./v. freebase) w. v. beasts beast Nilc0ntro1 24 1.83 NazSOr. 1.5% (=0.11mo1). 19l 0 18 do NQHzPOrZHzO, 3.3% (=0.21 m

TABLE 1 Rating Concentration 8 4 2 1 0 (expressed as No.0i Experimentpercent w./v. No. of animals in inicc- Total Ratc/ Hacmolysis No.L-tctrarmsole salt free base) each rating group tions rating beast testrating 1 Dihydrogen phosphate 12. 1 6 2 9 8 0,89 0 2. Dihydrogencitrat012. 75 1 5 2 1 El 16 1.78 0 3 Hydrogentartratc 12. 75 1 1 U 4 3 0 161,78 (1 TABLE 2 Rating C(onccntragion 16 8 4 2 1 0 expresse as No. oflIaemol sis Experiment percent w./v. N o. of animals in each injec-Total Rate} est No. L-tetramisole salt free base) rating group tionsrating beast rating 4 Dihydrogcn phosphate 12. 75 5 4 19 8 36 47 1 31 05. Hydrogen sulphate (prior art). 12. 75 1 6 16 11 2 O 36 152 4.2 3-4 6.Hydrochloride (prior art) 12.75 3 7 19 7 36 194 5.3 10 Acetate(priorart) 12.75 1 12 11 6 6 36 174 4.8 10

TABLE Concentration (expressed as Exp. percent w./v. N 0. 01 Rate] No.Formulation free base) beasts beast 19 L-tetramisole dihydrogen 12. 7594 0. 18

phosphate. 20 L-tetramisole dihydrogen 12. 75 U4 0. 03

phosphate plus 2.0% w./v. NaHzPOi (0.167 mol).

Examples 21 and 22 A further series of tests was carried out with anormal herd as described in Examples 19 and 20 using high concentrationsof both tetramisole salt and sodium salt. Results in Table 7 showexcellent acceptability in all instances.

TABLE 7 Tetramisole concentration (expressed as Exp. percent w./v. No.of Rate] No. Formulation free base) beasts beast 21 L-tetramisoledihydrogen 15. 3 40 0.

phosphate plus 2.54% w./v. N aHzPO; (0.212 mole). 22 L-tetramisoledihydrogen 30. 6 40 0.7

phosphate plus 5.08% w./v. N aHzPOt (0.424 mole).

Examples 23 25 Examples 19 and were performed on cattle grazing in areasof southern Australia which has a temperate climate. In the presentexample tests were made on herds of cattle in various areas ofQueensland having climates ranging from subtropical to tropical. Theanimals were injected with L- tetramisole dihydrogen phosphate solutionsprepared as in Example l. The solutions contained in addition 0.071 moleof sodium dihydrogen citrate and 0.142 mole of sodium dihydrogenphosphate dihydrate. The pH of the solutions was adjusted to a pH of 3.5by the addition of small amounts of phosphoric acid. The variousconcentrations of L-tetramisole dihydrogen phosphate used, the totalnumber of beasts tested and the rate per beast are set out in Table 8.The results of Table 8 demonstrate the excellent acceptability of thedihydrogen phosphate salt in the presence of sodium dihydrogen citrateunder the more arduous climatic conditions of Queensland.

TABLE 8 Concentration (expressed as Exp. percent w./v. N o. 01 Rate, No.lrtetramisole salt free base) beasts beast 23.- Dihydrogen phosphate 6.36 195 0. 62 24 .do. i 11. 6 318 1. 26

equivalent to 11.6 percent w/v of free base. The solutions were adjustedto a pH of 3.5 by the addition of phosphoric acid and contained inaddition 0.212 mole per liter of sodium dihydrogen citrate in solution(a) and 0.424 mole per liter of sodium dihydrogen citrate in solution(b). For each beast solution (a) was injected on one side and solution(b) on the other side. After 14 days the rate per beast was 0.45 forsolution (a) and Nil for solution (b). This example demonstrates theeffect of increased concentration of water soluble sodium salts in theformulation. Example 27 24 cattle taken from a normal herd were injectedwith L- tetramisole dihydrogen phosphate solutions as described inExamples 1 to 7. The concentration of L-tetramisole dihydrogen phosphatewas 17.3 percent w/v expressed as free base. The solution contained0.212 mole per liter of sodium dihydrogen phosphate and was adjusted topH 3.5 by the addition of phosphoric acid. The rate per beast was 2.6.

Example 28 Example 27 was repeated but the sodium dihydrogen phosphateof that example was replaced by 0.212 mole per liter of potassiumdihydrogen phosphate. The rate per beast was 2.2.

Example 29 12 cattle were injected with a solution prepared by themethod of examples 1 to 7. The formulation was L-tetramisole citratehaving a tetramisole concentration of 15.3 percent w/v expressed as freebase plus 0.212 mole/liter of Na H P0 2H O. The pH of the formulationwas adjusted to 3.5 by the addition of citric acid. The rate per beastwas 3.9.

Example 30 12 cattle were injected with a solution prepared by themethod of examples 1 to 7. The formulation was L-tetramisole tartratehaving a tetramisole concentration of 15.3 percent w/v expressed as freebase plus 0.212 mole/liter of Na ll PO. 21-1 0. The pH of theformulation was adjusted to 3.5 by the addition of tartaric acid. Therate per beast was 2.7.

We claim:

1. An aqueous solution, which is therapeutically acceptable to warmblooded animals by injection, said solution comprising tetramisolecitrate, tartrate or phosphate equivalent to at least 6 percent w/v ofL-tetramisole base, the pH of the solution being adjusted to the rangeof from 2 to 4 by addition of citric, tartaric or phosphoric acid.

2. An aqueous solution according to claim 1 wherein the tetramisolephosphate is L-tetramisole dihydrogen phosphate.

3. An aqueous solution according to claim 2 comprising L- tetramisoledihydrogen phosphate at concentrations from 12.5 w/v to the limit of itssolubility at the desired storage temperature.

4. An aqueous solution according to claim 2 comprising L- tetramisoledihydrogen phosphate, at concentrations in the range from 12.5 percentw/v to 23 percent w/v inclusive.

5. An aqueous solution according to claim 1 comprising from 0.1 to 0.5inclusive mole per liter of solution of a salt selected from the groupconsisting of a sodium or potassium salt of citric, tartaric orphosphoric acid.

6. A method of combating helminthiasis in a warm blooded animal whichmethod comprises injecting said animal with an effective amount of asolution according to claim 1.

7. A method of combating helminthiasis in a warm blooded animal whichmethod comprises injecting said animal with an effective amount of asolution according to claim 2.

8. A method of combating helminthiasis in a warm blooded animal whichmethod comprises injecting said animal with an effective amount of asolution according to claim 5.

2. An aqueous solution according to claim 1 wherein the tetramisolephosphate is L-tetramisole dihydrogen phosphate.
 3. An aqueous solutionaccording to claim 2 comprising L-tetramisole dihydrogen phosphate atconcentrations from 12.5 w/v to the limit of its solubility at thedesired storage temperature.
 4. An aqueous solution according to claim 2comprising L-tetramisole dihydrogen phosphate, at concentrations in therange from 12.5 percent w/v to 23 percent w/v inclusive.
 5. An aqueoussolution according to claim 1 comprising from 0.1 to 0.5 inclusive moleper liter of solution of a salt selected from the group consisting of asodium or potassium salt of citric, tartaric or phosphoric acid.
 6. Amethod of combating helminthiasis in a warm blooded animal which methodcomprises injecting said animal with an effective amount of a solutionaccording to claim
 1. 7. A method of combating helminThiasis in a warmblooded animal which method comprises injecting said animal with aneffective amount of a solution according to claim
 2. 8. A method ofcombating helminthiasis in a warm blooded animal which method comprisesinjecting said animal with an effective amount of a solution accordingto claim 5.